Optical fiber-based biosensors are an emerging field of research with an extremely broad area of possible applications and a disruptive potential to turn the paradigm known as lab-on-fiber into reality. In the past few years, a variety of system choices has been explored, ranging from the type of sensing fiber, to the optical transducing element, to possible sensing amplification strategies. We revise some of the possible approaches to the design of a biosensor, highlighting their advantages and disadvantages, based on previous literature and on the experience of our research groups. The discussion is focused onto DNA sensing systems, especially in a label-free format, where the hybridization and recognition of the sought DNA sequence is translated directly into a modification of the optical fiber properties.